Urinary incontinence, such as incontinence caused by bladder detrusor muscle instability, is a prevalent problem that affects people of all ages and levels of physical health, both in healthcare settings and in the community at large. At present, urinary incontinence afflicts 15-30% of elderly people living at home, one-third of those living in acute-care settings, and at least one-half of those in long-term care institutions (Resnick, R. M., Lancet 346:94 (1995)). Medically, it predisposes persons to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis. Psychosocially, urinary incontinence is associated with embarrassment, social stigmatization, depression, and with the risk of institutionalization (Herzo et al., Annu. Rev. Gerontol. Geriatr. 9:74 (1989)). Economically, the costs are great; in the United States alone, over $15 billion is spent per annum managing incontinence.
Treatments for incontinence include drugs with bladder relaxant properties, i.e., which help to control bladder detrusor muscle overactivity. Such drugs are effective in 80 to 85% of patients with uninhibited bladder contractions. Anticholinergic medications represent the mainstay of this type of treatment. The major proportion of the neurohumoral stimulus for physiologic bladder contraction is acetylcholine-induced stimulation of post ganglionic muscarinic receptor sites on bladder smooth muscle. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomine, have been used to treat urge incontinence. (See, e.g., Wein, A. J., Urol. Clin. N. Am. 22:557-577 (1995); Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J. 63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)).
However, none of the existing commercial drug treatments for incontinence has achieved complete success with all classes of incontinent patients, nor has treatment occurred without significant adverse (side) effects. For example, adverse effects, such as drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia which are related to the anticholinergic activity of such drugs, occur frequently and can be sufficiently troublesome to necessitate discontinuing treatment in up to 25% of patients, depending on the dosage. Yet, despite the occurrence of unwanted anticholinergic effects in many patients such drugs are currently prescribed for patients with bladder detrusor muscle hyperactivity when pharmacological therapy is indicated (Cf. Yarllur et al., Drugs Aging 6:243 (1995)).
The effects of acetylcholine are prevented when muscarinic receptor antagonists block its binding to muscarinic cholinergic receptors at certain neuroeffector sites such as in the urinary bladder (see Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 9th Ed. p. 148 (1996)).
Scopolamine, a muscarinic antagonist, has been reported to be effective, when administered transdermally, in the treatment of detrusor instability in female patients (Muskat et al., The Journal of Urology 156:1989-1990 (1996)). Muskat et al. state that when the drug is administered by an oral or systemic route, it causes severe side-effects and also discuss the contradictory reports regarding the transdermal administration of scopolamine. Muskat et al. report that although scopolamine is known to cause cycloplegia and dryness of the mouth, the side-effects in its study were not so severe to require discontinuation of the medication (Id. at 1990). Scopolamine is also reported as being used widely for motion sickness and as effective for the treatment of vertigo (Id.). However, it has also been reported that scopolamine has unwanted sedative effects (see Lathers et al., TIPS 10:243-250 (1989)).
Certain first generation H.sub.1 -receptor antihistamines, such as diphenylpyraline and promethazine, have been reported as having significant affinity for the muscarinic receptors (Kubo et al., Japan J. Pharmacol. 43:277-282 (1987)). Some first generation H.sub.1 receptor antihistamines, such as dimenhydrinate, cyclizine and meclizine, have also been found to be effective for treating either vertigo or motion sickness (Id; Wood, C., Drugs 17:471-479 (1979); Cohen et al., Archives of Neurology 27:129-135 (1972); see also Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 9th Ed. p. 588, 592 (1996)).
Peggs et al. (American Family Physician 52(2):593-600 (1995)), note that classic antihistamines, which have a greater propensity to cross the blood-brain barrier, would appear to be better indicated for the treatment of these conditions. However, the first generation H.sub.1 antihistamines have undesirable side-effects, such as sedation (see Goodman's & Gilman's, The Pharmacological Basis of Therapeutics, 9th Ed. p. 590 (1996).
The second generation H.sub.1 -receptor antihistamines, such as terfenadine, astemizole and loratadine, while having fewer sedative effects, are reported as having weak or no effect on muscarinic receptors (Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 9th Ed. p. 588 (1996); Simons, F. E., Drugs Safety 10(5):350-380 (1994)). This is consistent with the findings that such compounds do not possess any significant anticholinergic affects (see Simons, F. E., Drug Safety 10(5):350-380 (1994); Roman et al., Clinical Reviews in Allergy 11:89-110 (1993)). Quercia et al. (Hosp. Formul. 28:137-153 (1993)) reported that loratadine does not exhibit substantial anticholinergic or alpha-adrenergic effects since it has only a weak affinity for alpha-adrenoreceptor and acetylcholine receptors.
Astemizole has been reported to alleviate chronic vertigo (see Mitchelson F., Drugs 43(4):443-463 (1992)). However, astemizole and terfenadine have also been reported as ineffective at preventing motion sickness (Cheung et al., J. Clin. Pharmacol. 32:163-175 (1992)). Kohl et al. (J. Clin. Pharmacol. 31:934-946 (1991)) reported moderate efficacy of a single 300 mg dose of terfenadine (which is five fold higher than the recommended single dose) for motion sickness and pronounced individual response differences.
Kubo et al. (Japan J. Pharmacol. 43:277-282 (1987)) state that the anti-motion sickness activity of some of the H.sub.1 receptor antagonists may be related to their antimuscarinic ability. Kubo et al. also state that since histamine H.sub.1 receptor blockade is suggested to be associated with the sedative activity, a drug which has both antimuscarinic and antihistaminic effects may be more effective in the treatment of motion sickness.
Clinical efficacy trials indicated that loratadine is an effective H.sub.1 antagonist (see Clissold et al., Drugs 37:42-57 (1989)). Loratadine binds preferentially to peripheral rather than to central H.sub.1 receptors (Quercia et al., Hosp. Formul. 28:137-153 (1993)).
Loratadine is well absorbed but is extensively metabolized (Hilbert, et al., J. Clin. Pharmacol. 27:694-98 (1987)). The main metabolite, descarboethoxyloratadine, which has been identified, is reported to be pharmacologically active (Clissold, Drugs 37:4214 57 (1989)). It is also reported as having antihistaminic activity in U.S. Pat. No. 4,659,716. This patent recommends an oral dosage range of 5 to 100 mg/day and preferably 10 to 20 mg/day.
As explained, supra, the second generation H.sub.1 antagonists, such as loratadine, possess no or weak anticholinergic effects. Furthermore, astemizole and terfenadine, have been known to cause severe cardiac electrophysiologic adverse side-effects. These adverse side-effects are associated with a prolonged QT interval, and include, but are not limited to, ventricular fibrillation and cardiac arrhythmias, such as ventricular tachyarrhythmias or torsade de pointes. (Knowles, Canadian Journal Hosp. Pharm. 45:33,37 (1992); Craft, British Medical Journal 292:660 (1986); Simons et al., Lancet, 2:624 (1988); and Unknown, Side Effects of Drugs Annual 12:142 and 14:135). McCue, J. (Arch. Fam. Med. 5:464-468 (1996)) reports that loratadine does not appear to have adverse electrocardiographic effects.
Quercia et al. (Hosp. Formul. 28:137,142 (1993)) noted that serious cardiovascular adverse side-effects, including torsade de pointes and other ventricular arrhythmias, were reported in "healthy" patients who received terfenadine concurrently with either ketoconazole or erythromycin. Quercia et al. states that arrhythmias have also been reported with the concomitant administration of astemizole and erythromycin or erythromycin plus ketoconazole. Thus, he cautions against using loratadine concurrently with ketoconazole, itraconazole, and macrolides, such as erythromycin. McCue, J. (Arch. Fam. Med. 5:464-468 (1996)) reported that coadministration of loratadine with ketoconazole, erythromycin and cimetidine revealed no clinically relevant changes in cardiac repolarization or other electrocardiographic effects.
Additionally, it is known that ketoconazole, itraconazole, and/or erythromycin interfere with cytochrome P450, and thereby inhibit the metabolism of non-sedative antihistamines such as terfenadine, astemizole, and loratadine (see Andersen et al., Arch. Dermatol. 131:468-473 (1995)). Thus, there exists a potential for adverse interactions between loratadine and such drugs.
Brandes et al., (Cancer Res. (52):3796-3800 (1992)), showed that the propensity of drugs to promote tumor growth in vivo correlated with potency to inhibit concanavalin A stimulation of lymphocyte mitogenesis. Brandes et al., (J. Nat'l Cancer Inst. 86(10):771-775 (1994)), assessed loratadine in an in vitro assay to predict enhancement of in vivo tumor growth. This reference also reported that loratadine (at a dose of about 10 mg/day) and astemizole are associated with growth of both melanoma and fibrosarcoma tumors, in vivo.
Based upon the above discussion, it is clear that there is a need for an effective drug for the treatment of urinary incontinence, vertigo, and motion sickness which does not possess the adverse side-effects of the drugs previously prescribed for such disorders. There is also a need for a drug for the treatment of these conditions, which, in contrast to the second generation antihistamines, has anticholinergic activity, yet does not cause the adverse effects associated with administration of the first or second generation antihistamines.